A facile and general synthesis of 2β-aminosteroids

Article abstract of DOI:10.1055/s-0028-1088037

A facile and general synthesis of 2β-aminosteroids in high yields from 2,3α-epoxy-5α-androstan-17-one by regioselective aminolysis is developed using a zinc chloride/water catalytic system. The reaction is successful with both aliphatic and aromatic amine

Full text of DOI:10.1055/s-0028-1088037

PAPER
1255
A Facile and General Synthesis of 2b-Aminosteroids
Synthesis of
2b
-A
m
i
inoste
a
roids nbing Ke, Hao Hu, Dingshan Zhou, Wenjin Xu, Qifeng Zhu, Nimmanapalli Pulla Reddy, Xianming Hu*
State Key Laboratory of Virology, College of Pharmacy, Wuhan University, Wuhan 430072, P. R. of China
Fax +86(27)68754297; E-mail: xmhu@whu.edu.cn
Received 20 November 2008; revised 24 December 2008
An attractive route for the synthesis of 2b-aminosteroids
involves direct aminolysis of an epoxide. Ring-opening of
epoxides is a practical and widely used method for the
synthesis of b-amino alcohols.5 The synthesis of optically
pure epoxides from the corresponding alkenes is easy to
accomplish.6 We were therefore interested in the ring-
opening of steroidal epoxide 1 with various amines in
order to prepare axial 2b-aminosteroids of type 2
(Scheme 1). The most common method for the synthesis
of compounds 2 involves treatment of steroidal epoxides
with amines while heating in the presence of a catalytic
amount of water.2c,3a,7 1,2-Ethanediol has been used as the
solvent for the synthesis of 2-alkylamino-3-ol deriva-
tives.1d,8 Ionic liquids have been used both as solvents and
catalysts for the ring-opening of 2,3-epoxy steroids with
aromatic amines.9 The aminolysis of 5,6a- and 5,10a-ep-
oxy steroids in the presence of boron trifluoride diethyl
etherate has been reported.10 The ring-opening of hin-
dered 2,3a-epoxy steroids with amines has been per-
formed with a catalytic amount of gadolinium triflate
[Gd(OTf)3] in toluene, in a sealed tube, at high tempera-
ture under anhydrous conditions.11 4b-Aminocholestan-3-
ol is obtained from the corresponding 3,4a-epoxide by re-
action with ethanolic ammonia at 180 °C.12 However,
these methods do not overcome shortcomings such as
poor yields, long reaction times, operational intricacy,
toxic reagents, high pressure and expensive moisture/air-
sensitive catalysts. Hence, the development of a more ef-
ficient and simple method for the regioselective aminoly-
sis of steroidal epoxides would be of significant value. We
report herein the use of the zinc chloride/water catalytic
system to achieve this goal.
Abstract: A facile and general synthesis of 2b-aminosteroids in
high yields from 2,3a-epoxy-5a-androstan-17-one by regioselec-
tive aminolysis is developed using a zinc chloride/water catalytic
system. The reaction is successful with both aliphatic and aromatic
amines as well as with azoles.
Key words: amino alcohols, steroids, amines, epoxides, regiose-
lectivity
Aminosteroids are pharmaceutically important com-
pounds that display a broad spectrum of biological activi-
ty. A series of 2b-morpholinyl steroids has been shown to
possess anesthetic activity and several examples have
been selected for development as potential water-soluble
steroidal intravenous anesthetics.1 A steroid possessing a
2b-methylpiperazine moiety was reported to inhibit the
proliferation of HL-60 or WEHI-3B cell lines and is a
promising potential new drug for treatment of leukemia.2
The rigid steroid skeleton, substituted with amino groups
at different positions, provides an excellent means of
studying structure–activity relationships within a series of
neuromuscular blocking (NMB) agents.3 These studies,
carried out over the last forty years, have been very suc-
cessful in producing highly active and selective drugs
such as pancuronium, pipecuronium, vecuronium and
rocuronium which are widely used in clinical practice.
Another example, SZ-1677, which is related to rocuroni-
um, is in the preclinical phase. These NMB agents have
two acetylcholine-like (ACh-like) structural units located
at the C-2 position of the A-ring and the C-16 position of
the D-ring of the steroid. From many examples, it is clear
that the D-ring ACh mimic is the NMB pharmacophore
whereas the A-ring ACh moiety has muscarinic effects.3c
The muscarinic action generally results in undesirable
side-effects. Bronchospasm side-effects forced the with-
drawal of rapacuronium shortly after its clinical introduc-
tion in the United States despite its rapid onset and short
duration of action.4 As demonstrated with rapacuronium,
the important biological effects of the 2b-amino moiety
on the steroid A-ring have encouraged medicinal chemists
to synthesize and test a large number of novel molecules.
Considering that the inclusion of different amino groups
at the 2b-position of the steroid skeleton is an important
synthetic strategy in drug discovery, we have prepared a
number of 2b-aminosteroid derivatives.
O
O
R1
N
H
H
R1R2NH
R2
H
H
O
H
H
HO
H
H
2
1
R1, R2 = H, alkyl, aryl, etc.
Scheme 1 Synthesis of 2b-aminosteroids
We have developed methods using Lewis acid catalysts to
enhance the reactivity of epoxides towards nucleophilic
cleavage with amines.13 Extended heating in the presence
of zinc chloride/water resulted in good reactivity and high
regioselectivity in the ring-opening of epoxides with
amines. Using these fairly mild conditions, we reacted
2,3a-epoxy-5a-androstan-17-one 1 with various aliphatic
SYNTHESIS 2009, No. 8, pp 1255–1260
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088037; Art ID: F23508SS
© Georg Thieme Verlag Stuttgart · New York

1256
X. Ke et al.
PAPER
and aromatic amines and azoles and obtained the corre- firmed or conferred by consulting analyzing data of
sponding 2b-amino-3a-ols 2 in high yields (Table 1). The known compounds such as 2c14 and 2h.9 As anticipated,
structures and absolute configurations of 2 can be con- regioselective trans-diaxial epoxide opening led to the
formation of 2b-amino-3a-ols 2 and no regioisomeric 3b-
Table 1 Synthesis of 2b-Aminosteroids 2 via Reaction of Epoxide
amino-2a-ols were detected.
1 with Various Aminesa
Using water as the solvent, zinc-based catalysts proved to
Entry Amine
Time (h) Product Yield (%)b
be more effective than other water-soluble Lewis acids
such as tin tetrachloride (Table 2, entry 1) with respect to
yield and reaction time. We observed that zinc perchlorate
[Zn(ClO4)2] (Table 2, entry 2) was as potent as zinc chlo-
ride, however, the former is not recommended due to the
potential risk of explosion. We attempted to prepare imi-
dazolyl-substituted steroids under solvent-free conditions
according to a previous report,15 however, a very low
yield (7%) of the product was observed (Table 2, entry 3).
The same reaction was successful using the zinc chloride/
water system affording an excellent 96% yield of the ex-
pected product (Table 1, entry 17). When zinc chloride or
water were omitted, or the water was replaced with non-
polar or highly dipolar solvents (e.g. toluene or N,N-di-
methylformamide), or the zinc chloride was replaced with
hydrochloric acid or ammonium chloride, very low yields
of the product resulted (Table 2, entries 4–9). Therefore,
the zinc chloride/water system appears to be the best com-
bination for the regioselective aminolysis of steroidal ep-
oxides. In most cases, the products were extracted from
the aqueous phase using dichloromethane.
1
24
24
2a
2b
86
89
NH
2
3
4
NH
NH
24
24
2c
94
91
O
2d
Me
N
NH
5
6
24
24
2e
2f
90
84
NH2
MeO
NH2
7
24
2g
92
NH
Me
8
9
6
6
6
6
6
2h
2i
87
88
81
79
83
NH2
Table 2 Aminolysis of Epoxide 1 under Various Conditionsa
Entry Amine
Catalyst
SnCl4
Solvent Temp (°C)Yield (%)b
NH2
1
2
3
4
5
6
7
8
9
morpholine
H2O
100
100
80
84
93
7
10
11
12
2j
2k
2l
MeO
O2N
NH2
morpholine
imidazole
Zn(ClO4)2 H2O
–
–
NH2
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
–
H2O
–
100
110
110
110
100
100
14
6
HO
HO
NH2
ZnCl2
ZnCl2
ZnCl2
HCl
NH4Cl
toluene
DMF
H2O
H2O
4
13
14
15
6
6
2m
2n
2o
84
80
85
9
NH2
17
15
OH
NH2
a Reaction conditions: 1 (5 mmol), amine (15 mmol), catalyst (5
mmol), solvent (5 mL), 24 h.
b Yield of isolated product.
12
Me
N
H
The regioselectivity of the aminolysis of epoxide 1 and
formation of the 2b-configured product should principally
be influenced by the electronic and steric factors associat-
ed with the epoxide. In the area of Lewis acid catalyzed
ring-opening of epoxides in water, Fringuelli et al.16 have
reported significant results and have pointed out that the
regioselectivity and the reaction rate are influenced mark-
edly by the pH of the reaction medium and by the presence
of Lewis acids. Based on these results, we believe that the
N
16
17
8
8
2p
2q
93
96
NH
NH
N
a Reaction conditions: 1 (10 mmol), amine (30 mmol), ZnCl2 (10
mmol), H2O (10 mL), 100 °C.
b Yield of pure isolated product characterized by 1H NMR, 13C NMR
and MS spectroscopy.
Synthesis 2009, No. 8, 1255–1260 © Thieme Stuttgart · New York

PAPER
Synthesis of 2b-Aminosteroids
1257
Lewis acidity of zinc chloride plays a crucial role. The pH 2,3a-Epoxy-5a-androstan-17-one 1 was prepared according to the
literature.17 The amines and azoles were obtained from commercial
of our reactions was not regulated and they were per-
suppliers and used without further purification. Melting points were
formed at the pH obtained simply on mixing the reagents.
measured with an XT-4 apparatus and are uncorrected. 1H and 13
C
On the other hand, we believe that in water the Lewis
acids generate high concentrations of aqua ions which co-
ordinate the oxygen atom of the epoxide ring and/or the
nitrogen atom of the amine leading to significant acceler-
ation of nucleophilic attack. While one or more of the re-
actants appeared to dissolve poorly in water, emulsions
were formed upon addition of zinc chloride with stirring
and heating. It is likely these heterogeneous conditions fa-
cilitated the reaction progress leading to short reaction
times. Interestingly, the reaction times with aromatic
amines (Table 1, entries 8–17) were shorter than those
with aliphatic amines (Table 1, entries 1–7).
NMR spectra were obtained using a Bruker DPX400 apparatus and
CDCl3 or DMSO-d6 as solvent with TMS as the internal standard.
The 1H NMR data presented are for key protons in the steroid struc-
tures. Mass spectra were recorded on a Finnigan-LC Qadvantage
spectrometer (ESI). Elemental analysis (C, H, and N) data was ob-
tained using a VarioEL III elemental analyzer. Column chromatog-
raphy was performed using EM silica gel 60 (230–400 mesh). TLC
was performed on glass plates precoated with silica gel (5–40 mm).
Visualization was accomplished by spraying the TLC plates with a
solution of H2SO4–EtOH (1:10, v/v) and heating in an oven at 105
°C for 3 minutes (until the color had developed). Petroleum ether
(PE) refers to the fraction boiling in the 60–90 °C range.
3a-Hydroxy-2b-aminosteroids; General Procedure
The applicability of the zinc chloride/water catalytic sys-
tem was evaluated for the aminolysis of several simple ep-
oxides with various amines (Table 3). The excellent
yields obtained of the corresponding amino alcohols dem-
onstrates the efficiency of this catalytic system. It is rea-
sonable to assume that this mild Lewis acid catalyzed
aminolysis in water might represent an economical and
practical method for the synthesis of a wide range of b-
amino alcohols in addition to sterically hindered b-ami-
nosteroids.
To a mixture of epoxide 1 (10 mmol) and amine (30 mmol), a solu-
tion of ZnCl2 (10 mmol) in H2O (10 mL) was added. The mixture
was heated at 100 °C with vigorous magnetic stirring and the extent
of reaction was monitored by TLC. After completion of the reac-
tion, the mixture was concentrated under reduced pressure to give a
solid residue. Next, H2O (15 mL) was added and the organic mate-
rials were extracted with CH2Cl2 (3 × 10 mL). The combined organ-
ic layer was dried over anhyd Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by flash col-
umn chromatography on silica gel (PE–EtOAc–Et3N, or CH2Cl2–
MeOH–Et3N).
Table 3 Aminolysis of Simple Epoxides under Zinc Chloride/
3a-Hydroxy-2b-(1-pyrrolidinyl)-5a-androstan-17-one (2a)
Solid; mp 146–147 °C (Lit.7a 145–148 °C); Rf = 0.33 (PE–EtOAc,
1:2).
1H NMR (400 MHz, CDCl3): d = 0.85 (s, 3 H, H-18), 1.08 (s, 3 H,
H-19), 2.35 (m, 1 H, H-2), 2.53 (m, 4 H, NCH2), 4.05 (m, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 12.0, 12.9, 19.3, 20.8, 22.5, 26.7,
29.9, 30.6, 31.4, 33.6, 34.0, 34.9, 35.5, 38.3, 46.9, 50.6, 50.8, 54.3,
65.2, 66.9, 220.7.
Water Catalysisa
Entry Epoxide
1
Amine Productb
Yield (%)c
94
OH
N
H
N
O
O
O
MS (ESI): m/z (%) = 360 (100) [M + H+].
H
N
OH
Anal. Calcd for C23H37NO2: C, 76.83; H, 10.37; N, 3.90. Found: C,
77.11; H, 10.25; N, 3.87.
2
93
96
O
O
N
H
O
3a-Hydroxy-2b-(1-piperidinyl)-5a-androstan-17-one (2b)
Solid; mp 256–257 °C (Lit.7a 255–257 °C); Rf = 0.20 (PE–EtOAc,
1:2).
1H NMR (400 MHz, CDCl3): d = 0.86 (s, 3 H, H-18), 0.89 (s, 3 H,
H-19), 2.34–2.59 (m, 5 H, NCH2, H-2), 3.79 (m, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 13.1, 16.8, 19.9, 21.0, 24.2, 26.1,
27.5, 29.7, 30.9, 31.8, 34.2, 34.4, 35.05, 35.12, 37.6, 47.2, 48.7,
50.6, 55.5, 62.6, 64.3, 220.6.
H
N
OH
O
3
Cl
Cl
Cl
N
O
NH2
OH
H
N
O
4
91
Cl
MS (ESI): m/z (%) = 374 (100) [M + H+].
a Reaction conditions: epoxide (5 mmol), amine (15 mmol), ZnCl2 (10
mmol), H2O (5 mL), 8 h, 60 °C.
Anal. Calcd for C24H39NO2: C, 77.16; H, 10.52; N, 3.75. Found: C,
77.52; H, 10.33; N, 3.71.
b Structure determined by GCMS and NMR spectroscopy.
c Isolated yield.
3a-Hydroxy-2b-(4-morpholinyl)-5a-androstan-17-one (2c)
Solid; mp 171–173 °C (Lit.7a 170–172 °C); Rf = 0.32 (PE–EtOAc,
2:1).
1H NMR (400 MHz, CDCl3): d = 0.87 (s, 3 H, H-18), 0.91 (s, 3 H,
H-19), 2.42–2.65 (m, 4 H, NCH2), 2.56 (dd, J = 16.3, 8.6 Hz, 1 H,
H-2), 3.69 (m, 4 H, OCH2), 3.90 (m, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = 13.8, 16.3, 20.5, 21.7, 27.9, 30.5,
31.6, 32.5, 34.1, 34.9, 35.8, 35.9, 38.6, 47.8, 49.2, 51.3, 55.8, 63.8,
65.0, 67.3, 221.1.
In summary, we have reported a general and efficient
method for the regioselective preparation of 2b-amino-
steroids. The method offers advantages of operational
simplicity and high yields of products. Further studies on
the application of the present methodology to the synthe-
sis of biologically active compounds are in progress.
Synthesis 2009, No. 8, 1255–1260 © Thieme Stuttgart · New York

1258
X. Ke et al.
PAPER
MS (ESI): m/z (%) = 376 (100) [M + H+].
1H NMR (400 MHz, CDCl3): d = 0.82 (s, 3 H, H-18), 1.02 (s, 3 H,
H-19), 3.57 (br s, 1 H, H-2), 4.00 (br s, 1 H, H-3), 6.58 (d, J = 8.3
Hz, 2 H, H-2′,6′), 6.68 (t, J = 8.3 Hz, 1 H, H-4′), 7.16 (t, J = 8.3 Hz,
2 H, H-3′,5′).
Anal. Calcd for C23H37NO3: C, 73.56; H, 9.93; N, 3.73. Found: C,
73.68; H, 9.86; N, 3.67.
3a-Hydroxy-2b-(4-methyl-1-piperazinyl)-5a-androstan-17-one
13C NMR (100 MHz, CDCl3): d = 13.9, 15.1, 20.2, 21.7, 27.8, 30.7,
31.5, 32.1, 34.6, 35.8, 36.1, 38.3, 38.8, 47.9, 51.3, 54.4, 55.4, 68.3,
112.8, 117.4, 129.4, 147.1, 221.3.
(2d)
Solid; mp 180–181 °C (Lit.7b 180–181 °C); Rf = 0.41 (CH2Cl2–
MeOH, 8:1).
MS (ESI): m/z (%) = 382 (100) [M + H+].
1H NMR (400 MHz, CDCl3): d = 0.82 (s, 3 H, H-18), 0.84 (s, 3 H,
H-19), 2.26 (s, 3 H, NCH3), 2.40–2.67 (m, 9 H, NCH2, H-2), 3.85
(m, 1 H, H-3).
Anal. Calcd for C25H35NO2: C, 78.70; H, 9.25; N, 3.67. Found: C,
78.58; H, 9.29; N, 3.71.
13C NMR (100 MHz, CDCl3): d = 12.1, 15.2, 18.8, 20.0, 26.3, 28.8,
29.9, 30.9, 32.7, 33.3, 34.1, 34.2, 36.8, 44.3, 46.2, 49.6, 53.9, 54.3,
62.0, 62.7, 219.5.
3a-Hydroxy-2b-[(4-methylphenyl)amino]-5a-androstan-17-one
(2i)
Solid; mp 238–240 °C; Rf = 0.20 (PE–EtOAc, 4:1).
MS (ESI): m/z (%) = 389 (100) [M + H+].
1H NMR (400 MHz, CDCl3): d = 0.85 (s, 3 H, H-18), 1.01 (s, 3 H,
H-19), 2.23 (s, 3 H, CH3-4¢), 3.53 (br s, 1 H, H-2), 3.98 (br s, 1 H,
H-3), 6.50 (d, J = 8.3 Hz, 2 H, H-2¢, 6¢), 6.97 (d, J = 8.3 Hz, 2 H, H-
3¢, 5¢).
Anal. Calcd for C24H40N2O2: C, 74.18; H, 10.38; N, 7.21. Found: C,
74.34; H, 10.31; N, 7.17.
3a-Hydroxy-2b-[(phenylmethyl)amino]-5a-androstan-17-one
13C NMR (100 MHz, CDCl3): d = 13.9, 15.1, 20.2, 20.3, 21.7, 27.8,
30.7, 31.5, 32.1, 34.6, 35.8, 36.1, 38.4, 38.9, 47.9, 51.3, 54.7, 55.4,
68.4, 113.0, 126.6, 129.9, 144.9, 221.3.
(2e)
Solid; mp 139–140 °C; Rf = 0.50 (PE–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 0.84 (s, 3 H, H-18), 1.03 (s, 3 H,
H-19), 2.83 (br s, 1 H, H-2), 3.71–3.85 (m, 2 H, NCH2), 3.82 (br s,
1 H, H-3), 7.23–7.31 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.1, 14.1, 18.6, 20.0, 26.2, 29.1,
29.9, 30.8, 33.0, 34.1, 34.5, 37.3, 37.6, 46.2, 49.7, 50.7, 53.8, 57.6,
67.6, 125.2, 126.3, 126.7, 139.0, 219.8.
MS (ESI): m/z (%) = 396 (100) [M + H+].
Anal. Calcd for C26H37NO2: C, 78.94; H, 9.43; N, 3.54. Found: C,
79.13; H, 9.35; N, 3.48.
3a-Hydroxy-2b-[(4-methoxyphenyl)amino]-5a-androstan-17-
one (2j)
Solid; mp 197–198 °C; Rf = 0.11 (PE–EtOAc, 4:1).
MS (ESI): m/z (%) = 396 (100) [M + H+].
1H NMR (400 MHz, CDCl3): d = 0.85 (s, 3 H, H-18), 1.01 (s, 3 H,
H-19), 3.49 (br s, 1 H, H-2), 3.74 (s, 3 H, OCH3), 3.97 (m, 1 H, H-
3), 6.55 (d, J = 8.8 Hz, 2 H, H-2¢, 6¢), 6.77 (d, J = 8.8 Hz, 2 H, H-3¢,
5¢).
13C NMR (100 MHz, CDCl3): d = 13.4, 14.7, 19.7, 21.3, 27.4, 30.2,
31.1, 31.7, 34.2, 35.4, 35.7, 38.1, 38.4, 47.4, 50.9, 54.9, 55.0, 55.4,
68.0, 113.8, 114.6, 141.0, 151.7, 220.8.
Anal. Calcd for C26H37NO2: C, 78.94; H, 9.43; N, 3.54. Found: C,
78.81; H, 9.52; N, 3.57.
3a-Hydroxy-2b-{[(4-methoxyphenyl)methyl]amino}-5a-an-
drostan-17-one (2f)
Solid; mp 154–158 °C; Rf = 0.45 (PE–EtOAc–Et3N, 66:33:1).
1H NMR (400 MHz, CDCl3): d = 0.84 (s, 3 H, H-18), 1.02 (s, 3 H,
H-19), 2.81 (m, 1 H, H-2), 3.65–3.81 (m, 6 H, NCH2, OCH3, H-3),
6.48 (d, J = 8.4 Hz, 2 H, H-3′,5′), 7.22 (d, J = 8.4 Hz, 2 H, H-2′,6′).
13C NMR (100 MHz, CDCl3): d = 13.8, 14.6, 20.2, 21.7, 27.9, 30.7,
31.6, 32.5, 34.6, 35.8, 36.2, 38.8, 39.2, 47.9, 51.4, 51.7, 55.2, 55.4,
59.1, 69.1, 113.8, 129.2, 132.6, 158.6, 221.6.
MS (ESI): m/z (%) = 412 (100) [M + H+].
Anal. Calcd for C26H37NO3: C, 75.87; H, 9.06; N, 3.40. Found: C,
75.68; H, 9.09; N, 3.43.
3a-Hydroxy-2b-[(4-nitrophenyl)amino]-5a-androstan-17-one
(2k)
Solid; mp 246–247 °C; Rf = 0.35 (PE–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 0.86 (s, 3 H, H-18), 1.01 (s, 3 H,
H-19), 3.70 (br s, 1 H, H-2), 4.00 (m, 1 H, H-3), 6.52 (d, J = 9.2 Hz,
2 H, H-2¢, 6¢), 8.07 (d, J = 9.2 Hz, 2 H, H-3¢, 5¢).
13C NMR (100 MHz, CDCl3): d = 14.0, 15.1, 20.2, 21.8, 27.8, 30.6,
31.6, 32.2, 34.6, 35.9, 36.1, 37.5, 38.6, 47.9, 51.3, 54.0, 55.3, 67.7,
111.3, 126.6, 138.1, 152.2, 221.3.
MS (ESI): m/z (%) = 426 (100) [M + H+].
Anal. Calcd for C27H39NO3: C, 76.20; H, 9.24; N, 3.29. Found: C,
75.98; H, 9.37; N, 3.31.
3a-Hydroxy-2b-[methyl(phenylmethyl)amino]-5a-androstan-
17-one (2g)
Solid; mp 153–154 °C; Rf = 0.54 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 0.87 (s, 3 H, H-18), 0.90 (s, 3 H,
H-19), 2.13 (s, 3 H, NCH3), 2.82 (m, 1 H, H-2), 3.49–3.65 (m, 2 H,
NCH2), 3.91 (m, 1 H, H-3), 7.30 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.9, 17.4, 20.6, 21.7, 28.2, 30.4,
31.7, 32.3, 34.8, 35.1, 35.81, 35.84, 38.5, 47.9, 51.3, 56.2, 58.3,
63.7, 64.2, 127.1, 128.4, 128.7, 139.3, 221.3.
MS (ESI): m/z (%) = 427 (100) [M + H+].
Anal. Calcd for C25H34N2O4: C, 70.39; H, 8.03; N, 6.57. Found: C,
70.18; H, 7.92; N, 6.51.
3a-Hydroxy-2b-[(4-hydroxyphenyl)amino]-5a-androstan-17-
one (2l)
Solid; mp 241–243 °C; Rf = 0.42 (PE–EtOAc, 1:1).
1H NMR (400 MHz, DMSO-d6): d = 0.74 (s, 3 H, H-18), 0.90 (s, 3
H, H-19), 3.70 (br s, 1 H, H-2), 4.63 (m, 1 H, H-3), 6.41–6.54 (m, 4
H, ArH), 8.36 (s, 1 H, OH-4¢).
13C NMR (100 MHz, DMSO-d6): d = 13.4, 13.9, 19.7, 21.3, 27.6,
30.5, 31.3, 31.6, 33.9, 35.2, 35.5, 36.0, 38.4, 47.1, 50.5, 54.4, 55.0,
67.2, 113.6, 115.6, 140.7, 148.0, 219.8.
MS (ESI): m/z (%) = 410 (100) [M + H+].
Anal. Calcd for C27H39NO2: C, 79.17; H, 9.60; N, 3.42. Found: C,
78.93; H, 9.67; N, 3.56.
3a-Hydroxy-2b-(phenylamino)-5a-androstan-17-one (2h)
Solid; mp 220–221 °C; Rf = 0.42 (PE–EtOAc, 2:1).
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Synthesis of 2b-Aminosteroids
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MS (ESI): m/z (%) = 398 (100) [M + H+].
1H NMR (400 MHz, CDCl3): d = 0.70 (s, 3 H, H-18), 0.84 (s, 3 H,
H-19), 4.17 (m, 1 H, H-2), 4.31 (m, 1 H, H-3), 6.96 (s, 2 H, H-4¢,
5¢), 7.44 (s, 1 H, H-2¢).
13C NMR (100 MHz, CDCl3): d = 13.8, 14.9, 20.5, 21.7, 27.7, 30.4,
31.5, 34.4, 34.7, 35.8, 36.0, 39.1, 41.9, 47.8, 51.2, 55.3, 58.7, 67.2,
117.4, 128.9, 136.1, 221.1.
Anal. Calcd for C25H35NO3: C, 75.53; H, 8.87; N, 3.52. Found: C,
75.81; H, 8.64; N, 3.47.
3a-Hydroxy-2b-[(3-hydroxyphenyl)amino]-5a-androstan-17-
one (2m)
Solid; mp 238–239 °C; Rf = 0.33 (PE–EtOAc, 1:1).
MS (ESI): m/z (%) = 357 (100) [M + H+].
1H NMR (400 MHz, DMSO-d6): d = 0.73 (s, 3 H, H-18), 0.87 (s, 3
H, H-19), 3.72 (br s, 1 H, H-2), 4.69 (m, 1 H, H-3), 5.93 (d, J = 7.9
Hz, 2 H, H-6′), 5.99 (s, 1 H, H-2′), 6.02 (d, J = 7.9 Hz, 1 H, H-4′),
6.81 (t, J = 7.9 Hz, 1 H, H-5′), 8.85 (s, 1 H, OH-3¢).
Anal. Calcd for C22H32N2O2: C, 74.12; H, 9.05; N, 7.86. Found: C,
73.91; H, 9.11; N, 7.82.
13C NMR (100 MHz, DMSO-d6): d = 13.4, 13.9, 19.8, 21.3, 27.7,
30.5, 31.3, 31.6, 33.9, 35.2, 35.5, 38.4, 47.1, 50.5, 53.4, 54.9, 67.4,
99.0, 102.8, 103.9, 129.3, 149.0, 158.1, 219.8.
Acknowledgment
Helpful suggestions from Professor Richard M. Kellogg (Universi-
ty of Groningen, Netherlands) and Dr. Zhaokui Wan (Wyeth
Research, USA) are gratefully acknowledged.
MS (ESI): m/z (%) = 398 (100) [M + H+].
Anal. Calcd for C25H35NO3: C, 75.53; H, 8.87; N, 3.52. Found: C,
75.74; H, 8.80; N, 3.51.
References
3a-Hydroxy-2b-[(2-hydroxyphenyl)amino]-5a-androstan-17-
one (2n)
Solid; mp 172–173 °C; Rf = 0.34 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 0.85 (s, 3 H, H-18), 1.05 (s, 3 H,
H-19), 3.55 (br s, 1 H, H-2), 4.02 (br s, 1 H, H-3), 6.57–6.84 (m, 4
H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.9, 14.9, 20.2, 21.7, 27.8, 30.7,
31.5, 32.1, 34.6, 35.9, 36.0, 38.6, 38.9, 48.0, 51.3, 54.5, 55.4, 68.4,
111.5, 114.2, 117.3, 121.7, 136.5, 143.8, 222.1.
(1) (a) Hewett, C. L.; Savage, D. S.; Lewis, J. J.; Sugrue, M. F.
J. Pharm. Pharmacol. 1964, 16, 765. (b) Daniell, C. J.;
Cross, M.; Sneyd, J. R.; Thompson, P.; Wiedeman, M. M.
Br. J. Anaesth. 1996, 76, 586. (c) Hill-Venning, C.; Peters,
J. A.; Callachan, H.; Lambert, J. J.; Gemmell, D. K.;
Anderson, A.; Byford, A.; Hamilton, N.; Hill, D. R.;
Marshall, R. J.; Campbell, C. Neuropharmacology 1996, 35,
1209. (d) Anderson, A.; Boyd, A. C.; Byford, A.; Campbell,
A. C.; Gemmell, D. K. J. Med. Chem. 1997, 40, 1668.
(2) (a) He, Q.; Jiang, D. Leukemia Res. 1999, 23, 369. (b) He,
Q.; Na, X. Leukemia Res. 2001, 25, 455. (c) Roy, J.; Deroy,
P.; Poirier, D. J. Comb. Chem. 2007, 9, 347. (d) Thibeault,
D.; Roy, J.; Deroy, P.; Poirier, D. Bioorg. Med. Chem. Lett.
2008, 16, 5062.
MS (ESI): m/z (%) = 398 (100) [M + H+].
Anal. Calcd for C25H35NO3: C, 75.53; H, 8.87; N, 3.52. Found: C,
75.41; H, 8.95; N, 3.56.
(3) (a) Buckett, W. R.; Hewett, C. L.; Savage, D. S. J. Med.
Chem. 1973, 16, 1116. (b) Tuba, Z.; Maho, S. Curr. Med.
Chem. 2002, 9, 1507. (c) Lee, C. Pharmacol. Therapeut.
2003, 98, 143. (d) Gyermek, L. Med. Res. Rev. 2005, 25,
610. (e) Zlotos, D. P. Mini-Rev. Med. Chem. 2005, 5, 595.
(4) (a) Levy, J. H.; Pitts, M.; Thanopoulos, A.; Szlam, F.; Kim,
J. Anesth. Analg. 1999, 89, 290. (b) Naguib, M.
Anesthesiology 2001, 94, 924.
(5) (a) Hanson, R. M. Chem. Rev. 1991, 91, 437. (b) Azizi, N.;
Saidi, M. R. Org. Lett. 2005, 7, 3649. (c) Shivani; Pujala,
B.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 3713 and
references cited therein.
3a-Hydroxy-2b-[methyl(phenyl)amino]-5a-androstan-17-one
(2o)
Solid; mp 157–158 °C; Rf = 0.60 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 0.85 (s, 3 H, H-18), 0.91 (s, 3 H,
H-19), 2.74 (s, 3 H, NCH3), 3.91 (dd, J = 19.0, 10.2 Hz, 1 H, H-2),
4.10 (m, 1 H, H-3), 6.80 (t, J = 8.2 Hz, 1 H, H-4′), 6.91 (d, J = 8.2
Hz, 2 H, H-2′,6′), 7.24 (t, J = 8.2 Hz, 2 H, H-3′,5′).
13C NMR (100 MHz, CDCl3): d = 12.5, 16.2, 19.2, 20.4, 26.8, 29.0,
29.4, 30.2, 33.7, 33.8, 34.4, 34.6, 34.9, 37.5, 46.5, 49.9, 54.6, 59.8,
63.8, 113.7, 117.0, 127.8, 149.9, 219.7.
MS (ESI): m/z (%) = 396 (100) [M + H+].
(6) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(7) (a) Hewett, C. L.; Savage, D. S. J. Chem. Soc. C 1968, 9,
1134. (b) He, Q.; Xu, Y. H. Acta Pharmacol. Sin. 1992, 27,
101.
Anal. Calcd for C26H37NO2: C, 78.94; H, 9.43; N, 3.54. Found: C,
78.61; H, 9.57; N, 3.49.
(8) Murphy, W. S.; Sarsam, B. J. Chem. Soc., Perkin Trans. 1
1999, 3311.
3a-Hydroxy-2b-(1H-pyrazol-1-yl)-5a-androstan-17-one (2p)
Solid; mp 212–213 °C; Rf = 0.19 (PE–EtOAc–Et3N, 66:33:1).
(9) Horvath, A.; Skoda-Foldes, R.; Maho, S.; Berente, Z.;
1H NMR (400 MHz, CDCl3): d = 0.69 (s, 3 H, H-18), 0.84 (s, 3 H,
H-19), 4.32 (m, 1 H, H-2), 4.62 (m, 1 H, H-3), 6.26 (m, 1 H, H-4¢),
7.45 (d, J = 2.1 Hz, 1 H, H-5¢), 7.52 (d, J = 1.4 Hz, 1 H, H-3¢).
13C NMR (100 MHz, CDCl3): d = 13.9, 14.8, 20.6, 21.8, 27.8, 30.6,
31.6, 34.2, 34.8, 35.88, 35.94, 39.3, 41.6, 47.9, 51.4, 55.5, 62.2,
67.4, 105.4, 128.9, 139.0, 221.3.
Kollar, L. Steroids 2006, 71, 706.
(10) (a) Ponsold, K.; Schade, W.; Wunderwald, M. J. Prakt.
Chem. 1975, 317, 307. (b) Agarwal, V.; Husain, S.; Gupta,
K. C. J. Indian Chem. Soc. 1995, 72, 639.
(11) Thibeault, D.; Poirier, D. Synlett 2003, 1192.
(12) Svoboda, M.; Tichy, M.; Fajkos, J.; Sicher, J. Tetrahedron
Lett. 1962, 3, 717.
MS (ESI): m/z (%) = 357 (100) [M + H+].
(13) Ke, X.; Hu, H.; Zhang, K.; Xu, W.; Zhu, Q.; Wu, L.; Hu, X.
Anal. Calcd for C22H32N2O2: C, 74.12; H, 9.05; N, 7.86. Found: C,
74.36; H, 8.98; N, 7.75.
Chem. Commun. 2009, 1037.
(14) Fielding, L.; Grant, G. H. J. Am. Chem. Soc. 1991, 113,
9785.
(15) Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron 2007, 63,
469.
3a-Hydroxy-2b-(1H-imidazol-1-yl)-5a-androstan-17-one (2q)
Solid; mp 224–226 °C; Rf = 0.44 (EtOAc–MeOH–Et3N, 93:6:1).
Synthesis 2009, No. 8, 1255–1260 © Thieme Stuttgart · New York

1260
X. Ke et al.
PAPER
(16) (a) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2000, 311.
(b) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001,
66, 4719. (c) Fringuelli, F.; Pizzo, F.; Vaccaro, L.
F.; Tortoioli, S.; Vaccaro, L. Synlett 2003, 2292.
(i) Fringuelli, F.; Pizzo, F.; Rucci, M.; Vaccaro, L. J. Org.
Chem. 2003, 68, 7041. (j) Fringuelli, F.; Pizzo, F.; Tortoioli,
S.; Vaccaro, L. J. Org. Chem. 2003, 68, 8248. (k) Bonollo,
S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2007, 2683.
(l) Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett
2008, 1574.
Tetrahedron Lett. 2001, 42, 1131. (d) Fringuelli, F.; Pizzo,
F.; Vaccaro, L. J. Org. Chem. 2001, 66, 3554.
(e) Amantini, D.; Fringuelli, F.; Pizzo, F.; Vaccaro, L.
J. Org. Chem. 2001, 66, 4463. (f) Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Adv. Synth. Catal. 2002, 344, 379.
(g) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Green
Chem. 2003, 5, 436. (h) Amantini, D.; Fringuelli, F.; Pizzo,
(17) (a) Wolf, G. C.; Robert, T. B. J. Org. Chem. 1976, 41, 1254.
(b) Yan, Z. H.; Tian, W. S. Tetrahedron Lett. 2004, 45, 2211.
Synthesis 2009, No. 8, 1255–1260 © Thieme Stuttgart · New York